Classification of sharks in the Egyptian Mediterranean waters using morphological and DNA barcoding approaches.
The identification of species constitutes the first basic step in phylogenetic studies, biodiversity monitoring and conservation. DNA barcoding, i.e. the sequencing of a short standardized region of DNA, has been proposed as a new tool for animal species identification. The present study provides an update on the composition of shark in the Egyptian Mediterranean waters off Alexandria, since the latest study to date was performed 30 years ago, DNA barcoding was used in addition to classical taxonomical methodologies. Thus, 51 specimen were DNA barcoded for a 667 bp region of the mitochondrial COI gene. Although DNA barcoding aims at developing species identification systems, some phylogenetic signals were apparent in the data. In the neighbor-joining tree, 8 major clusters were apparent, each of them containing individuals belonging to the same species, and most with 100% bootstrap value. This study is the first to our knowledge to use DNA barcoding of the mitochondrial COI gene in order to confirm the presence of species Squalus acanthias, Oxynotus centrina, Squatina squatina, Scyliorhinus canicula, Scyliorhinus stellaris, Mustelus mustelus, Mustelus punctulatus and Carcharhinus altimus in the Egyptian Mediterranean waters. Finally, our study is the starting point of a new barcoding database concerning shark composition in the Egyptian Mediterranean waters (Barcoding of Egyptian Mediterranean Sharks [BEMS], http://www.boldsystems.org/views/projectlist.php?&#Barcoding%20Fish%20%28FishBOL%29).


Disease network delineates the disease progression profile of cardiovascular diseases.
As Electronic Health Records (EHR) data accumulated explosively in recent years, the tremendous amount of patient clinical data provided opportunities to discover real world evidence. In this study, a graphical disease network, named progressive cardiovascular disease network (progCDN), was built to delineate the progression profiles of cardiovascular diseases (CVD). The EHR data of 14.3 million patients with CVD diagnoses were collected for building disease network and further analysis. We applied a new designed method, progression rates (PR), to calculate the progression relationship among different diagnoses. Based on the disease network outcome, 23 disease progression pair were selected to screen for salient features. The network depicted the dominant diseases in CVD development, such as the heart failure and coronary arteriosclerosis. Novel progression relationships were also discovered, such as the progression path from long QT syndrome to major depression. In addition, three age-group progCDNs identified a series of age-associated disease progression paths and important successor diseases with age bias. Furthermore, a list of important features with sufficient abundance and high correlation was extracted for building disease risk models. The PR method designed for identifying the progression relationship could be widely applied in any EHR database due to its flexibility and robust functionality. Meanwhile, researchers could use the progCDN network to validate or explore novel disease relationships in real world data. The first-time interrogation of such a huge CVD patients cohort enabled us to explore the general and age-specific disease progression patterns in CVD development.


The inhibition of caeruloplasmin by cyanide.
1. The reversible inhibition of the oxidase activity of caeruloplasmin by cyanide was investigated. 2. The kinetics are unusual, being competitive but with the inhibited complex formed only during cycling. 3. Inhibitory concentrations of cyanide are comparable with that of caeruloplasmin. 4. One azide group completely inhibits a caeruloplasmin molecule but two cyanide groups are required. 5. The results suggest that azide binds to a half-reduced or fully reduced conformational isomer of the enzyme whereas cyanide binds to completely reoxidized isomers, and that inhibited complexes contain ligand bridges between copper atoms.


Buddlejasaponin IV induces cell cycle arrest at G2/M phase and apoptosis in immortalized human oral keratinocytes.
Buddlejasaponin IV (BS-IV), a major component of Pleurospermum kamtschaticum, exerts antiinflammatory and cytotoxic effects against cancer cells. The study investigated whether BS-IV could prevent oral carcinogenesis by inhibiting the growth of immortalized human oral keratinocytes (IHOKs). BS-IV reduced cell viability and induced cell cycle arrest at G2/M phase and apoptotic morphological changes in IHOKs. BS-IV inhibited the levels of cyclin B1, Cdc2 and Cdc25C, but enhanced Chk2 phosphorylation. The increased levels of pRb and p21 protein and the activation of p53 were also noted in BS-IV-treated IHOKs. In addition, BS-IV induced cytochrome c release from mitochondria by reducing antiapoptotic Bcl-2 levels and increasing pro-apoptotic Bax levels. BS-IV treatment resulted in the activation of caspase-9 and caspase-3. PARP cleavage was also clearly observed in the BS-IV-treated IHOKs. Furthermore, the expression of the Fas death receptor and Fas ligand was induced and procaspase-8 level was suppressed by BS-IV treatment. Taken together, BS-IV treatment inhibited the growth of IHOK cells via the induction of p53-dependent cell cycle arrest at the G2/M phase and apoptosis via both mitochondrial-dependent and death receptor-mediated pathways. Thus, BS-IV can be considered an excellent candidate for a chemopreventive agent to block the progression of HPV-induced oral carcinogenesis.


Unsupervised Pathology Detection: A Deep Dive Into the State of the Art.
Deep unsupervised approaches are gathering increased attention for applications such as pathology detection and segmentation in medical images since they promise to alleviate the need for large labeled datasets and are more generalizable than their supervised counterparts in detecting any kind of rare pathology. As the Unsupervised Anomaly Detection (UAD) literature continuously grows and new paradigms emerge, it is vital to continuously evaluate and benchmark new methods in a common framework, in order to reassess the state-of-the-art (SOTA) and identify promising research directions. To this end, we evaluate a diverse selection of cutting-edge UAD methods on multiple medical datasets, comparing them against the established SOTA in UAD for brain MRI. Our experiments demonstrate that newly developed feature-modeling methods from the industrial and medical literature achieve increased performance compared to previous work and set the new SOTA in a variety of modalities and datasets. Additionally, we show that such methods are capable of benefiting from recently developed self-supervised pre-training algorithms, further increasing their performance. Finally, we perform a series of experiments in order to gain further insights into some unique characteristics of selected models and datasets. Our code can be found under https://github.com/iolag/UPD_study/.


Surface Hydrophobicity and Guest Permeability in Polydimethylsiloxane-Coated MIL-53 as Studied by Solid-State Nuclear Magnetic Resonance Spectroscopy.
Experimental characterization of the hydrophobic porous materials at the atomic and molecular levels is of great significance, but exploring their hydrophobicity characteristics and interactions with guest molecules with distinct polarity is still challenging. In this work, solid-state NMR is employed to characterize the surface hydrophobicity and explore the guest solvent permeability in polydimethylsiloxane (PDMS)-coated MIL-53. It was found that the PDMS-coated MIL-53 was hydrophobic to water and infiltrated to methanol, acetone, benzene, toluene, and ethylbenzene solvents. In addition, two types of guest solvents (methanol, acetone, benzene, toluene, and ethylbenzene), inside the pore and outside the pore of PDMS-coated MIL-53, were clearly identified using two-dimensional 1H-1H homo-nuclear correlation NMR experiments. Moreover, the membrane thickness of the PDMS-coated MIL-53 could be determined from the analysis of the 1H-1H spin diffusion buildup curves. Furthermore, the permeability of benzene, toluene, and ethylbenzene at different PDMS coating levels was extracted from 1H MAS NMR. The increase of the hydrophobic PDMS layer resulted in a decrease of the penetration of aromatic guests to the internal pore of MIL-53. This work provides deep insights into the understanding of guest solvent permeability of hydrophobic layer-coated MOFs in the application fields of catalysis and separation.


Spatial patterns of aflatoxin levels in relation to ear-feeding insect damage in pre-harvest corn.
Key impediments to increased corn yield and quality in the southeastern US coastal plain region are damage by ear-feeding insects and aflatoxin contamination caused by infection of Aspergillus flavus. Key ear-feeding insects are corn earworm, Helicoverpa zea, fall armyworm, Spodoptera frugiperda, maize weevil, Sitophilus zeamais, and brown stink bug, Euschistus servus. In 2006 and 2007, aflatoxin contamination and insect damage were sampled before harvest in three 0.4-hectare corn fields using a grid sampling method. The feeding damage by each of ear/kernel-feeding insects (i.e., corn earworm/fall armyworm damage on the silk/cob, and discoloration of corn kernels by stink bugs), and maize weevil population were assessed at each grid point with five ears. The spatial distribution pattern of aflatoxin contamination was also assessed using the corn samples collected at each sampling point. Aflatoxin level was correlated to the number of maize weevils and stink bug-discolored kernels, but not closely correlated to either husk coverage or corn earworm damage. Contour maps of the maize weevil populations, stink bug-damaged kernels, and aflatoxin levels exhibited an aggregated distribution pattern with a strong edge effect on all three parameters. The separation of silk- and cob-feeding insects from kernel-feeding insects, as well as chewing (i.e., the corn earworm and maize weevil) and piercing-sucking insects (i.e., the stink bugs) and their damage in relation to aflatoxin accumulation is economically important. Both theoretic and applied ramifications of this study were discussed by proposing a hypothesis on the underlying mechanisms of the aggregated distribution patterns and strong edge effect of insect damage and aflatoxin contamination, and by discussing possible management tactics for aflatoxin reduction by proper management of kernel-feeding insects. Future directions on basic and applied research related to aflatoxin contamination are also discussed.


Potential enhanced association between obstructive lung disease and history of depression in patients with diabetes.
Depression is one of the most common comorbidities of chronic diseases including diabetes and obstructive lung diseases (emphysema, chronic bronchitis, and asthma). Obstructive lung diseases and depression have few symptoms in common. However, they are both common in adults and associated with chronic inflammation. It is not clear if their coappearance in diabetic patients is coincidental or associated beyond that expected by chance. A total of 1,003 adults with diabetes in community practice settings were interviewed at home at the time of their enrolment into the Vermont Diabetes Information System, a clinical decision support program. Patients self-reported their personal and clinical characteristics, including any obstructive lung disease. Laboratory data were obtained directly from the clinical laboratory, and current medications were obtained by direct observation of medication containers. We performed a cross-sectional analysis of the interviewed subjects to assess a possible association between the prevalence of obstructive lung disease and depression. In a multivariate logistic regression model, obstructive lung disease was significantly associated with depression even after correcting for gender, obesity (≥30 kg/m2), high comorbidities (>2), low annual income (<$30,000/ year), cigarette smoking, alcohol problems, and education level (odds ratio=1.83; 95% confidence interval 1.27, 2.62; P <0.01). These data suggest a potential enhanced association between obstructive lung disease and depression in patients with diabetes. Future studies are needed to identify if inflammation is implicated in this association as a common denominator.


[Treatment of palpebral ptosis with frontal suspension: a comparative study of different materials].
The aim of this study was to compare the results of three materials used for frontal muscle suspension in the treatment of palpebral ptosis. Sixty-six eyes in 46 patients with palpebral ptosis were operated with a modified Fox technique. The suspension was performed with autologous fascia lata in 18 cases (group 1), cryopreserved fascia lata in 23 cases (group 2), silicone in 15 cases (group 3), and PTFE in 20 cases (group 4). The results were evaluated according to the height symmetry of the palpebral opening and the improvement in visual capacity. The results were considered satisfactory in 16 patients (88%) in group 1, 19 cases (82%) in group 2, 12 cases (80%) in group 3, and 18 cases (90%) in group 4. Complications included the loss of correction with recurrent palpebral ptosis requiring revision surgery, or foreign body granuloma formation. The highest complication rate occurred in group 4 (40%), and the lowest in group 1 (5%). Two thirds of the patients with recurrent ptosis were included in the group of younger patients. Autologous or homologous fascia lata is superior to silicone or PTFE when used as a suspension material in the treatment of palpebral ptosis.


Nonpermissive HLA-DPB1 mismatch increases mortality after myeloablative unrelated allogeneic hematopoietic cell transplantation.
We examined current outcomes of unrelated donor allogeneic hematopoietic cell transplantation (HCT) to determine the clinical implications of donor-recipient HLA matching. Adult and pediatric patients who had first undergone myeloablative-unrelated bone marrow or peripheral blood HCT for acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, and myelodysplastic syndrome between 1999 and 2011 were included. All had high-resolution typing for HLA-A, -B, -C, and -DRB1. Of the total (n = 8003), cases were 8/8 (n = 5449), 7/8 (n = 2071), or 6/8 (n = 483) matched. HLA mismatch (6-7/8) conferred significantly increased risk for grades II to IV and III to IV acute graft vs host disease (GVHD), chronic GVHD, transplant-related mortality (TRM), and overall mortality compared with HLA-matched cases (8/8). Type (allele/antigen) and locus (HLA-A, -B, -C, and -DRB1) of mismatch were not associated with overall mortality. Among 8/8 matched cases, HLA-DPB1 and -DQB1 mismatch resulted in increased acute GVHD, and HLA-DPB1 mismatch had decreased relapse. Nonpermissive HLA-DPB1 allele mismatch was associated with higher TRM compared with permissive HLA-DPB1 mismatch or HLA-DPB1 match and increased overall mortality compared with permissive HLA-DPB1 mismatch in 8/8 (and 10/10) matched cases. Full matching at HLA-A, -B, -C, and -DRB1 is required for optimal unrelated donor HCT survival, and avoidance of nonpermissive HLA-DPB1 mismatches in otherwise HLA-matched pairs is indicated.


Physiology of hypokinetic and hyperkinetic movement disorders: model for dyskinesia.
Although the basal ganglia have been implicated in the development of movement disorders since the 1940s, the exact role played by these structures has remained elusive. The development of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-monkey model of parkinsonism, and the recent resurgence of surgical therapy for the treatment of hypokinetic and hyperkinetic movement disorders has, however, led to an improved understanding of the pathophysiological mechanisms that underlie their development. In this article, we review the functional organization and examine the changes in neuronal activity that occur in the basal ganglia thalamocortical 'motor' circuit in these disorders. An alternative to the classic 'rate' model for Parkinson's disease is presented that incorporates the observed changes in neuronal activity, as well as additional neuronal pathways that contribute to these changes. Based on studies in animal models and humans with hyperkinetic movement disorders, it is postulated that dyskinesias develop as the result of a combination of excessive reductions in the mean discharge rate, altered patterns and increased synchronization of neurons in the internal segment of the globus pallidus. It is further postulated that the particular type of involuntary movement which develops also depends on the relative change in neuronal activity in the direct, indirect and alternative pathways. Support for these postulates is examined, and models for drug-induced dyskinesia, hemiballismus and dystonia are proposed.


Noncontrast and perfusion CT provides accurate assessment of head deceleration injury.
To investigate the feasibility of noncontrast computed tomography (NcCT) and perfusion CT (PCT) in the assessment of head deceleration injury (HDI). A small animal HDI device was developed. A total of 20 healthy adult rabbits with frontal impacts resulting from a 3.5 m drop were included in this study. All subjects underwent NcCT and PCT scans 12 hours before injury and three to four hours after head injury. Brain injuries were evaluated by traditional macroscopic and microscopic examination after CT scans. Microscopic examination revealed hemorrhagic cerebral contusions in 14 subjects and cerebral parenchyma hyperemia in 6 subjects. Contrecoup injuries were more severe than the coup injuries in this study. As verified by pathoanatomical observations, NcCT effectively revealed all of the calvarial fractures and basal skull fractures in 12 subjects. Furthermore, most rabbits suffered acute scalp contusions, subarachnoid hemorrhages and cerebral contusions. PCT analysis revealed much larger and more severe contusions when compared to those observed via NcCT. The combination of NcCT and PCT could be an effective approach for detection of acute cerebral contusions, which can provide sufficient experimental evidence for accurate clinical diagnosis and prognosis of HDI.


Travelling at a slug's pace: possible invertebrate vectors of Caenorhabditis nematodes.
How do very small animals with limited long-distance dispersal abilities move between locations, especially if they prefer ephemeral micro-habitats that are only available for short periods of time? The free-living model nematode Caenorhabditis elegans and several congeneric taxa appear to be common in such short-lived environments, for example decomposing fruits or other rotting plant material. Dispersal is usually assumed to depend on animal vectors, yet all current data is based on only a limited number of studies. In our project we performed three comprehensive field surveys on possible invertebrate vectors in North German locations containing populations of C. elegans and two related species, especially C. remanei, and combined these screens with an experimental analysis of persistence in one of the vector taxa. Our field survey revealed that Caenorhabditis nematodes are commonly found in slugs, isopods, and chilopods, but are not present in the remaining taxonomic groups examined. Surprisingly, the nematodes were frequently isolated from the intestines of slugs, even if slugs were not collected in close association with suitable substrates for Caenorhabditis proliferation. This suggests that the nematodes are able to enter the slug intestines and persist for certain periods of time. Our experimental analysis confirmed the ability of C. elegans to invade slug intestines and subsequently be excreted alive with the slug feces, although only for short time periods under laboratory conditions. We conclude that three invertebrate taxonomic groups represent potential vectors of Caenorhabditis nematodes. The nematodes appear to have evolved specific adaptations to enter and persist in the harsh environment of slug intestines, possibly indicating first steps towards a parasitic life-style.


Evidence for consistent patterns between flavonoid structures and cellular activities.
A wide variety of plant-derived compounds, including the polyphenolic flavonoids, is present in the human diet or is consumed for medicinal reasons. Epidemiological and animal studies tend to suggest a protective effect of flavonoids against cardiovascular diseases and some types of cancer. Although flavonoids have been studied for about 50 years, the cellular mechanisms involved in their biological activity are still largely unknown. Antioxidant properties of the flavonoids have been postulated as a mechanism for putative protective effect against cardiovascular disease. Nevertheless, these properties alone are not sufficient to explain the anti-carcinogenic potential of these polyphenols. The mechanisms by which the molecules interact with cells or are absorbed by them are very important for determining the intracellular concentration and distribution of the metabolites to internal organs. With the exception of the cells lining the gastrointestinal tract, all other cells in the body are only exposed to flavonoid metabolites and degradation products. No previous studies have addressed this aspect of cellular exposure, except for some methylated metabolites. Within the last decade, reports on flavonoid activities have been largely associated with enzyme inhibition and anti-proliferative activity. From our recent work on the human colon cancer cell line HT29 and comparison with published studies, structure-function relationships demonstrate that antioxidant, enzyme inhibitor or anti-proliferative activities are dependent on particular structure motifs. The present review also presents a summary of mechanistic data on a few elected compounds.


Early-career researchers: an interview with Michael Rosario.
Michael Rosario is an Assistant Professor at West Chester University, USA, where he studies elastic mechanisms in biology. He received his undergraduate degree in Integrative Biology from the University of California, Berkeley, USA, in 2009 before completing his Master's degree in Organismic and Evolutionary Biology at the University of Massachusetts, Amherst, USA, in 2013 and his PhD in Biology at Duke University, USA, in 2015. Rosario completed a National Science Foundation Postdoctoral Fellowship with Tom Roberts at Brown University, USA, before moving to West Chester University in 2018.


Physical activity across the curriculum: year one process evaluation results.
Physical Activity Across the Curriculum (PAAC) is a 3-year elementary school-based intervention to determine if increased amounts of moderate intensity physical activity performed in the classroom will diminish gains in body mass index (BMI). It is a cluster-randomized, controlled trial, involving 4905 children (2505 intervention, 2400 control). We collected both qualitative and quantitative process evaluation data from 24 schools (14 intervention and 10 control), which included tracking teacher training issues, challenges and barriers to effective implementation of PAAC lessons, initial and continual use of program specified activities, and potential competing factors, which might contaminate or lessen program effects. Overall teacher attendance at training sessions showed exceptional reach. Teachers incorporated active lessons on most days, resulting in significantly greater student physical activity levels compared to controls (p < 0.0001). Enjoyment ratings for classroom-based lessons were also higher for intervention students. Competing factors, which might influence program results, were not carried out at intervention or control schools or were judged to be minimal. In the first year of the PAAC intervention, process evaluation results were instrumental in identifying successes and challenges faced by teachers when trying to modify existing academic lessons to incorporate physical activity.


Anisotropic behaviours of droplets impacting on dielectrowetting substrates.
The spreading of a sessile droplet on a solid substrate is enhanced if a non-uniform electric field is applied at the contact-line region. This so-called dielectrowetting effect holds great potential in controlling the spreading of droplets by varying the strength of the electric field. In this paper, we experimentally and theoretically study the effect of the dielectrowetting on the dynamics of droplets impacting on a solid surface having electrodes to impose the non-uniform electric field to the liquid. We experimentally study the anisotropic behaviours in both the spreading and retracting stages: the droplets spread more but retract with significantly smaller rates in the direction parallel to the electrodes. We provide a theoretical explanation for the spreading enhancement caused by dielectrowetting by decoupling it from inertia-induced spreading. We also theoretically account for the reduction in retraction rate using force balance at the contact line. The theoretical analysis in both the spreading and retracting stages is verified experimentally.


Empirical Study on Human Movement Classification Using Insole Footwear Sensor System and Machine Learning.
This paper presents a plantar pressure sensor system (P2S2) integrated in the insoles of shoes to detect thirteen commonly used human movements including walking, stooping left and right, pulling a cart backward, squatting, descending, ascending stairs, running, and falling (front, back, right, left). Six force sensitive resistors (FSR) sensors were positioned on critical pressure points on the insoles to capture the electrical signature of pressure change in the various movements. A total of 34 adult participants were tested with the P2S2. The pressure data were collected and processed using a Principal Component Analysis (PCA) for input to the multiple machine learning (ML) algorithms, including k-NN, neural network and Support-Vector Machine (SVM) algorithms. The ML models were trained using four-fold cross-validation. Each fold kept subject data independent from other folds. The model proved effective with an accuracy of 86%, showing a promising result in predicting human movements using the P2S2 integrated in shoes.


The Measurement of Bovine Pericardium Density and Its Implications on Leaflet Stress Distribution in Bioprosthetic Heart Valves.
Bioprosthetic Heart Valves (BHVs) are widely used in clinical practice, showing promising outcomes. Computational modeling offers a valuable tool for quantitatively characterizing BHVs. To ensure the accuracy of computational models, it is crucial to consider precise leaflet properties, including mechanical properties and density. Bovine pericardium (BP) serves as a common material for BHV leaflets. Previous computational studies often assume BP density to approximate that of water or blood. Given that BP leaflets undergo various treatments, such as tissue fixation and anti-calcification, this study aims to measure the density of BP used in BHVs and assess its impact on leaflet stress distribution. Eight square BP samples were laser cut from Edwards BP patches and their density was determined. Specimen weight was measured using an A&D Analytical Balance, while volume was assessed through high-resolution imaging. Additionally, finite element models resembling a BHV, like the Carpentier-Edwards PERIMOUNT Magna, were constructed in ABAQUS. The average density of the BP samples was found to be 1,410 kg/m3. During the acceleration phase of a cardiac cycle, the maximum stress reached 1.89 MPa for a density of 1,410 kg/m3 and 2.47 MPa for a density of 1,000 kg/m3 (a 30.7% difference). In the deceleration phase, the maximum stress reached 713 kPa and 669 kPa, respectively. Leaflet stress distribution and motion in BHVs are influenced by density variations. Establishing an accurate density value for BHV leaflets is imperative for enhancing the computational models, which can ultimately contribute to improved BHV design and outcomes.


Derivation of clinical prediction rules to identify children with fractures after twisting injuries of the ankle.
The authors sought to derive maximally sensitive prediction rules for identifying children with significant fractures after acute twisting injuries to the ankle. The authors prospectively enrolled a convenience sample of patients younger than 18 years of age who presented to the pediatric emergency department of an urban, tertiary care center after sustaining acute twisting injuries of the ankle. The ankle was defined in two regions: the malleolar zone and the midfoot zone. Clinical findings were documented on standardized data collection sheets by faculty physicians before completion of ankle and/or foot radiograph series. Significant fracture was defined a priori as any fracture other than an avulsion < or =3 mm. The authors conducted binary recursive partitioning with cross-validation to develop models to predict fracture. Data from 717 enrolled patients with a median age of 12.9 years were analyzed. Significant malleolar zone and midfoot zone fractures were diagnosed in 81 of 682 (11.9%) and 10 of 173 (5.8%) patients for whom ankle and foot radiographs were obtained. Recursive partitioning identified patients at low risk for malleolar zone fracture if 1) they had no bone tenderness at either malleolus or the region just proximal to the fibula malleolus or 2) they had bone tenderness at either malleolus but were able to walk four steps in the emergency department and had no swelling at either malleolus. The two-part malleolar zone rule had a sensitivity of 100% and specificity of 19.1% on the learning data and 95.1% (95% confidence interval [95% CI] = 87.8% to 98.6%) and 20.0% (95% CI = 16.8% to 23.4%) on the test data. Tenderness either at the proximal fifth metatarsal or cuboid identified midfoot zone fractures with a sensitivity of 100% and specificity of 31.9% on the learning data and 90.0% (95% CI = 55.4% to 99.7%) and 35.0% (95% CI = 27.7% to 42.8%) on the test sample. A set of sensitive prediction rules was developed to identify children with significant fractures after twisting injuries to the ankle. External validation and refinement of the rules will be needed before recommendation of widespread use.


[The role radiography in assessing the stage of renal cancer].
The investigation included 421 cases of renal cell carcinoma with metastases of different localization. Tumor advancement was assessed by application of general-view imaging, X-ray, computed and magnetic resonance tomography, ultrasound and osteoscintigraphy. Alterations in the lung were registered in 271 patients (64.4%); metastases into bones--244 (57.9%). Tumor dissemination to retroperitoneal lymph nodes was detected in 166, liver--96 and the brain--6 patients.


Science and product.
Much of what needs to be changed in U.S. industry involves close ties to manufacturing, design for manufacturability, a rapid design cycle, and up-to-date technical knowledge on the part of the engineers themselves. Being up-to-date requires conscious company effort. Traveling to meetings, reading the technical literature, and being a part of the engineering community are necessities if we are to compete with others who make these efforts and are thus better able to incorporate technical change rapidly into their own products. Outside the product improvement cycle, a research (as opposed to development) organization in industry must have close ties to development and manufacturing in order to succeed. With these close ties, researchers can understand the progress of the cycle and can introduce new steps at the appropriate time and in an acceptable form. A research organization that surmounts the internal barriers and becomes an accepted contributor to the development and manufacturing process can, because of its greater technical depth, its scientific knowledge, and its close ties with the university world, become a forceful initiator of progress. It is more difficult, in our opinion, to make these contributions from a university base and from government laboratories as they are now constituted. Much has been said by industry and government leaders about reforming the educational system and strengthening the national science base-things that help build a strong foundation. A strong science base supplies a vast storehouse of new ideas, and a good educational system provides engineers and manufacturing workers with knowledge; but strength here cannot make up for inadequacies in the functioning of the development and manufacturing cycle. The United States must learn to succeed, not only in the ladder type of innovation in which a wholly new idea from science creates a wholly new product (the science-dominated process at which we have succeeded in the past), but also in the rapid, cyclical, engineer-dominated process of incremental product improvement. Neither process is a substitute for the other; we need both.


Snails go on a fast when acetylsalicylic acid comes along with heat stress: A possible effect of HSPs and serotonergic system on the feeding response.
A novel food followed by sickness, causes a taste-specific conditioned aversion, known as the 'Garcia effect'. We recently found that both a heat shock stressor (30 °C for 1 h - HS) and the bacterial lipopolysaccharide (LPS) can be used as 'sickness-inducing' stimuli to induce a Garcia effect in the pond snail Lymnaea stagnalis. Additionally, if snails are exposed to acetylsalicylic acid (ASA) present in aspirin tablets before the LPS injection, the formation of the Garcia effect is prevented. Here, we hypothesized that exposing snails to crushed aspirin before the HS (ASA-HS) would prevent the HS-induced 'sickness state' and - therefore -the Garcia effect. Unexpectantly, the ASA-HS procedure induced a generalized and long-lasting feeding suppression. We thus investigate the molecular effects underlying this phenomenon. While the exposure to the HS alone resulted in a significant upregulation of the mRNA levels of the Heat Shock Protein 70 (HSP 70) in snails' central ring ganglia, the ASA-HS procedure induced an even greater upregulation of HSP70, suggesting that the ASA-HS combination causes a severe stress response that inhibits feeding. Additionally, we found that the ASA-HS procedure induced a significant downregulation of the mRNA levels of genes involved with the serotoninergic system which regulates feeding in snails. Finally, the ASA-HS procedure prevented HS-induced upregulation of the mRNA levels of key neuroplasticity genes. Our study indicates that two sickness-inducing stimuli can have different physiological responses even if behavioral outcomes are similar under some learning contexts.


Wormwood (Artemisia absinthium) suppresses tumour necrosis factor alpha and accelerates healing in patients with Crohn's disease - A controlled clinical trial.
Suppression of tumour necrosis factor alpha (TNF-alpha) and other interleukins by wormwood (Artemisia absinthium) extracts were reported recently in in vitro studies. The aim of the present study was to find out if this effect can be also be observed in Crohn's Disease (CD) patients where TNF-alpha appears to play an important role. In a controlled trial, 10 randomly selected patients suffering from CD were given in addition to their basic CD therapy 3x750mg dried powdered wormwood for 6 weeks. Ten patients, also randomly selected who met the inclusion criteria served as control group. Minimum score of 200 on Crohn's Disease Activity Index (CDAI) was required at baseline for inclusion in each group. Patients who received infliximab or similar were excluded from the trial. TNF-alpha level in serum were measured at baseline, and after three and six weeks. During this period all concomitant CD medications was maintained at the baseline dose levels. Average serum TNF-alpha level fell from 24.5+/-3.5pg/ml at baseline to 8.0+/-2.5pg/ml after six weeks. The corresponding levels in the control group were 25.7+/-4.6 (week 0), and 21.1+/-3.2 (week 6). On the clinical side, CDAI scores fell from 275+/-15 to below 175+/-12 in wormwood group with remission of symptoms in eight patients (CDAI score below 170 or reduction by 70 points), compared to only two in the placebo group (CDAI of placebo group 282+/-11 at baseline and 230+/-14 on week 6). IBDQ also reflected accelerated clinical response with wormwood. Of clinical significance were the findings that wormwood also improved mood of the CD patients, as reflected in Hamilton's Depression Scale. These findings provide a base to test wormwood in clinical conditions thought to be mediated by increased production of pro-inflammatory cytokines such as TNF-alpha.


Associations Between Life's Essential 8 and Abdominal Aortic Calcification Among Middle-Aged and Elderly Populations.
Abdominal aortic calcification (AAC) is an independent risk factor for cardiovascular disease. We aim to examine the associations between Life's Essential 8 (LE8), the recently updated measurement of cardiovascular health (CVH), and AAC among participants aged ≥40 years. This population-based cross-sectional study used data from the National Health and Nutrition Examination Survey in 2013 to 2014. AAC (AAC score>0) and severe AAC (AAC score>6) were quantified by the Kauppila score system. Multiple linear, multivariable logistic, and restricted cubic spline models were used to assess the associations. A total of 2369 participants were included with a mean AAC score of 1.41 (0.13). Participants in the high-cardiovascular-health group had lower AAC scores, lower prevalence of AAC, and lower prevalence of severe AAC. After the adjustment of potential confounders (age, sex, race and ethnicity, education levels, marital status, poverty income ratio, estimated glomerular filtration rate, serum creatinine, serum uric acid, serum phosphorus, and serum total calcium), higher cardiovascular health was significantly associated with lower risk of AAC. Meanwhile, elevated nicotine exposure score, blood glucose score, and blood pressure score within the LE8 components were significantly associated with lower risk of AAC. Also, nonlinear dose-response relationships were observed. Subgroup analyses (age strata, sex, poverty income ratio, education levels, marital status) indicated the inverse associations of LE8 and AAC were generally similar in different populations. LE8 was negatively and nonlinearly related to the risk of AAC among middle-aged and older populations. Meanwhile, LE8 components should prioritize higher scores for nicotine exposure, blood glucose, and blood pressure evaluations.


Factors related to haloperidol response and dyskinesias in autistic children.
A secondary analysis of data pooled from three studies (Anderson et al. 1984, 1989; Campbell et al. 1978) was performed to identify variables predictive of haloperidol response in 125 autistic children, with ages ranging from 2.3 to 8.2 years. Mean behavioral improvement was greater under haloperidol treatment conditions than under placebo. Higher intelligence quotient (IQ) was predictive of reduction in behavioral symptoms under general conditions of haloperidol or placebo treatment, while older children were found to respond favorably to haloperidol itself. Under both haloperidol and placebo conditions, there was also a tendency for greater reduction in symptoms, in terms of raw score and percent change, for those with greater initial severity of illness. Results for initial severity of illness as a predictor of improvement generalized across a wide variety of behavior not specific to autism (e.g., hyperactivity and temper outbursts). However, mean behavioral improvement and its prediction with demographics for individuals tended to be more specific to symptoms related to autism per se. Reduction in symptoms during short-term haloperidol treatment was not found to be related to whether or not children developed dyskinesias in subsequent long-term haloperidol administration.


Treatment of actinic keratoses with sequential combination of 5-fluorouracil and photodynamic therapy.
Actinic keratoses (AKs) are traditionally treated with cryotherapy, curettage, and 5-fluorouracil (5-FU, Efudex, ICN Pharmaceuticals, Inc.), all of which are associated with adverse effects. Although photodynamic therapy (PDT) with topical 5-aminolevulinic acid (ALA) offers a treatment alternative, current protocols require 14 to 18 hours incubation with ALA and patients experience pain during light treatment. Fifteen patients with multiple and diffuse facial AKs applied 5-FU nightly for 5 days and underwent PDT with ALA (Levulan Kerastick, Dusa Pharmaceuticals, Inc.) on the sixth day. ALA was applied to their entire faces and remained in contact with the skin for 30 to 45 minutes under low-intensity visible light. After removing ALA, faces received a single pass of 560- to 1200-nm intense pulsed light (VascuLight or Lumenis One, Lumenis). At 1 month and at 1 year post-treatment, 90% of treated AKs had resolved in all but one patient. Erythema resolved 7 to 10 days after treatment. Patients with multiple diffuse AKs may benefit from the application of 5-FU for 5 days followed by ALA-PDT with intense pulsed light activation.


Phosphorylation, maturational processing, and relatedness of strain Colburn matrix proteins.
The intracellular 66,000 D (66K) and 69,000 D (69K) matrix-like phosphoproteins of strain Colburn cytomegalovirus (CMV) have been compared with each other and with their electrophoretic counterparts in the virion. Three lines of evidence indicate that the 66K and 69K proteins are products of separate genes, and that the intracellular and virion species are closely related. First, "pulse-chase" radiolabeling experiments showed that these proteins have separate precursors; that modification of each to the mature form correlated with phosphorylation; and that phosphorylation of the 69K precursor occurred more slowly than that of the 66K precursor, and resulted in a more dramatic slowing of its electrophoretic mobility. Second, comparisons of the 66K and 69K proteins based on partial proteolysis of [35S]methionine-labeled proteins, using V8 protease, and complete proteolysis of [32P]orthophosphate-labeled proteins, using trypsin or Pronase, provided no evidence of sequence relatedness. These analyses also suggested that the distribution of phosphorylated residues differs in the two proteins--clustered for the 69K and more disperse for the 66K. Phosphoamino acid analyses showed only phosphoserine in the 66K protein. The 69K protein contained, in addition to phosphoserine, an electrophoretically faster moving, unidentified spot. And third, immunological comparisons showed these proteins to exhibit little or no antigenic cross-reactivity. They did, however, demonstrate that the nuclear proteins are immunologically cross-reactive with their respective virion counterparts. Additional comparisons of these nuclear and virion proteins established that the virion 69K protein (v69) differs in electrophoretic mobility and net charge from the nuclear 69K protein but that it, as well as the virion 66K protein, has a two-dimensional phosphopeptide pattern similar to its nuclear counterpart.


DVT and pulmonary embolism: Part I. Diagnosis.
The incidence of venous thromboembolic diseases is increasing as the U.S. population ages. At least one established risk factor is present in approximately 75 percent of patients who develop these diseases. Hospitalized patients and nursing home residents account for one half of all cases of deep venous thrombosis. A well-validated clinical prediction rule can be used for risk stratification of patients with suspected deep venous thrombosis. Used in combination with D-dimer or Doppler ultrasound tests, the prediction rule can reduce the need for contrast venography, as well as the likelihood of false-positive or false-negative test results. The inclusion of helical computed tomographic venography (i.e., a below-the-pelvis component) in pulmonary embolism protocols remains under evaluation. Specific combinations of a clinical prediction rule, ventilation-perfusion scanning, and D-dimer testing can rule out pulmonary embolism without an invasive or expensive investigation. A clinical prediction rule for pulmonary embolism is most helpful when it is used with subsequent evaluations such as ventilation-perfusion scanning, D-dimer testing, or computed tomography. Technologic advances are improving the resolution of helical computed tomography to allow detection of smaller emboli; however, further study is needed to provide definitive evidence supporting the role of this imaging technique in the diagnosis of pulmonary embolism. D-dimer testing is helpful clinically only when the result is negative. A negative D-dimer test can be used in combination with a clinical decision rule, ventilation-perfusion scanning, and/or helical computed tomography to lower the probability of pulmonary embolism to the point that aggressive treatment is not required. Evidence-based algorithms help guide the diagnosis of deep venous thrombosis and pulmonary embolism.


A cognitive heuristic algorithm for reseau mark detection by hill climbing.
A hill-climbing approach for the automatic detection of Reseau marks (RM) on the vidicon type of imagery is presented. This procedure is based on the minimization of a figure of merit which is a measure of the clustering nature of the gray values of the Reseau pixels around a nominal value. The often-encountered problem of false detection is circumvented by incorporating the concept of ``learning'' the mean gray value of the RM pixels. Results of applying the algorithm to both synthetic and actual imagery demonstrate the efficacy of the proposed method.


ROS, stress-activated kinases and stress signaling in cancer.
Anticancer therapy is frequently efficient in early stages of the disease, whereas advanced tumors are usually resistant to the same treatments. The molecular basis for this change is not entirely understood. Many anticancer agents are DNA- or cytoskeleton-damaging drugs that show some specificity towards dividing cells. However, recent studies show that these agents also activate stress-signaling cascades that may play a role in eliciting the observed therapeutic effects. We discuss recent findings that suggest that induction of stress signaling in oncogenically transformed cells is integrated into apoptotic pathways. Reactive oxygen species (ROS) and stress-activated protein kinases (SAPKs), which are potentiated in recently transformed cells, emerge as key effectors of cell death. In advanced tumors, however, these agents are downregulated and, consequently, death signaling is suppressed. Such changes in ROS and SAPK activity levels during the course of tumor development may underlie the changes in responsiveness to anticancer therapy.


Projections of the effects of climate change on allergic asthma: the contribution of aerobiology.
Climate change is unequivocal and represents a possible threat for patients affected by allergic conditions. It has already had an impact on living organisms, including plants and fungi with current scenarios projecting further effects by the end of the century. Over the last three decades, studies have shown changes in production, dispersion and allergen content of pollen and spores, which may be region- and species-specific. In addition, these changes may have been influenced by urban air pollutants interacting directly with pollen. Data suggest an increasing effect of aeroallergens on allergic patients over this period, which may also imply a greater likelihood of the development of an allergic respiratory disease in sensitized subjects and exacerbation of symptomatic patients. There are a number of limitations that make predictions uncertain, and further and specifically designed studies are needed to clarify current effects and future scenarios. We recommend: More stress on pollen/spore exposure in the diagnosis and treatment guidelines of respiratory and allergic diseases; collection of aerobiological data in a structured way at the European level; creation, promotion and support of multidisciplinary research teams in this area; lobbying the European Union and other funders to finance this research.


Catastrophic failure after open reduction internal fixation of femoral neck fractures with a novel locking plate implant.
To determine if the use of a novel proximal femoral locking plate could reduce the incidence of femoral neck shortening and improve clinical outcomes after open reduction internal fixation (ORIF) for femoral neck fractures as compared with historical controls. Single surgeon, retrospective case-control study. Academic level I trauma center. Twenty-one femoral neck fractures treated with the posterolateral femoral locking plate (Synthes, Inc, Paoli, PA) were eligible for inclusion. Eighteen met inclusion/exclusion criteria with a mean follow-up of 16 months. ORIF of femoral neck fracture with the posterolateral femoral locking plate. This consists of a side plate with multiple locking screws directed into the femoral head at converging/diverging angles and a single shaft screw. Intraoperative compression was achieved with partially threaded screws before locking screw insertion. Maintenance of reduction was assessed by comparing immediate postoperative and final follow-up radiographs. Clinical outcome was assessed with Harris Hip Scores after 1 year. Complications and secondary operations were noted. Seven (36.8%) of 18 patients experienced catastrophic failure. Five of these patients required total hip replacement, whereas the remaining 2 died before further treatment. The remaining 11 patients (61.1%) achieved bony union; the average displacement of the center of the head did not differ when compared with historical controls (0.78 mm inferiorly, 1.62 mm medially, and 2.4 degrees of increased varus vs. 0.86 mm, 1.23 mm, and 0.6 degree). Complications in this group include 1 instance of screw fracture, 2 total hip replacements, and a peri-implant subtrochanteric femur fracture. The average patient age and proportion of displaced fractures did not differ between the historical control and experimental groups. Fracture displacement was strongly associated with catastrophic failure in the experimental group only. Average Harris Hip Scores was significantly worse compared with that of historical controls (67.9 vs. 84.7, P = 0.05). ORIF of femoral neck fractures using a locking plate construct yielded unacceptably poor outcomes in this patient population. We hypothesize that the stiffness of this construct prevents any fracture site micromotion, placing the mechanical burden on the implant, which can result in failure at the bone-screw interface or fatigue failure of the implant itself.


Lateral extensions of the Müller muscle.
To define the lateral extension of the Müller muscle and to elucidate its involvement in the development and surgical treatment of Graves (thyroid) eye disease. Twelve lateral halves of orbits exenterated from patients with medial or posterior orbital neoplasms were fixed, embedded, and step sectioned at 250-microns intervals to produce histological sections. Gross anatomical dissections of human cadaver heads were also used to corroborate the histological findings. Histological analysis revealed that the Müller muscle extended laterally between the orbital and palpebral lobes of the lacrimal gland in all specimens. The smooth muscle fibers were found to interdigitate with lacrimal ducts passing from the orbital to palpebral lobe and to extend close to the ductal orifices at the conjunctival surface. Gross dissections confirmed that the Müller muscle accompanied the levator aponeurosis lateral extension, which is known to pass between the orbital and palpebral lobes of the lacrimal gland. Our anatomical findings suggest that the Müller muscle may contribute to the temporal flare frequently seen in eyelid retraction associated with thyroid eye disease. They may also explain the difficulty of treating lateral eyelid retraction in thyroid eye disease and indicate the need for new surgical approaches for severe lateral eyelid retraction.


Three-dimensional telomere architecture of esophageal squamous cell carcinoma: comparison of tumor and normal epithelial cells.
Telomeres are repetitive nucleotide sequences (TTAGGG)n located at the ends of chromosomes that function to preserve chromosomal integrity and prevent terminal end-to-end fusions. Telomere loss or dysfunction results in breakage-bridge-fusion cycles, aneuploidy, gene amplification and chromosomal rearrangements, which can lead to genomic instability and promote carcinogenesis. Evaluating the hypothesis that changes in telomeres contribute to the development of esophageal squamous cell carcinoma (ESCC) and to determine whether there are differences between young and old patients, we compared the three-dimensional (3D) nuclear telomere architecture in ESCC tumor cells with that of normal epithelial cells obtained from the same patient. Patients were equally divided by age into two groups, one comprising those less than 45 years of age and the other consisting of those over 80 years of age. Tumor and normal epithelial cells located at least 10 cm from the border of the tumor were biopsied in ESCC patients. Hematoxylin and eosin staining was performed for each sample to confirm and identify the cancer and normal epithelial cells. This study was based on quantitative 3D fluorescence in situ hybridization (Q-FISH), 3D imaging and 3D analysis of paraffin-embedded slides. The 3D telomere architecture data were computer analyzed using 100 nuclei per slide. The following were the main parameters compared: the number of signals (number of telomeres), signal intensity (telomere length), number of telomere aggregates, and nuclear volume. Tumor and normal epithelial samples from 16 patients were compared. The normal epithelial cells had more telomere signals and higher intensities than the tumor cells, with P-values of P < 0.0001 and P = 0.0078, respectively. There were no statistically significant differences in the numbers of telomere aggregates or the nuclear volumes between the tumor and normal epithelial cells. Secondary analyses examined the effects of age on 3D telomere architecture and found no statistically significant differences in any parameter tested between the young and old patients in either the tumor or epithelial cells. The 3D nuclear telomeric signature was able to detect differences in telomere architecture between the ESCC and normal epithelial tissues. However, there were no differences observed between the young and old patients.


Maximal indirect development, set-aside cells, and levels of selection.
The evolution of metazoan development as described by Davidson et al. (1995. Science 270:1319-1325) is readily interpretable in terms of levels-of-selection conflicts, for instance, as recently modeled by Michod (1999. Darwinian Dynamics, Princeton, NJ: Princeton University Press). Davidson et al. propose certain features of early bilaterians including small size, a small and fixed number of cell divisions during and subsequent to cleavage, and specification of cell fates prior to cell movement. These features suggest constraints on certain parameters of Michod's model, specifically t (the time available for cell division) and b (the benefit to cells of not cooperating in terms of their rate of replication). Such constraints clearly enhance between-cell cooperation and allow multicellularity to more easily evolve and be maintained. Nevertheless, these constraints are completely abrogated by the phenomenon of "set-aside cells," that is, undifferentiated cells that retain indefinite division potential. Levels-of-selection theory predicts that the evolution of these set-aside cells must be accompanied by features which alleviate cell-cell competition, and indeed the results of Ransick et al. (1996. Proc Natl Acad Sci USA 93:6759-6763) support this prediction: the evolution of "set-aside cells" in metazoans was accompanied by the evolution of the sequestration of the germ line.


Neuronal population models reveal specific linear conductance controllers sufficient to rescue preclinical disease phenotypes.
Preclinical drug candidates are screened for their ability to ameliorate in vitro neuronal electrophysiology, and go/no-go decisions progress drugs to clinical trials based on population means across cells and animals. However, these measures do not mitigate clinical endpoint risk. Population-based modeling captures variability across multiple electrophysiological measures from healthy, disease, and drug phenotypes. We pursued optimizing therapeutic targets by identifying coherent sets of ion channel target modulations for recovering heterogeneous wild-type (WT) population excitability profiles from a heterogeneous Huntington's disease (HD) population. Our approach combines mechanistic simulations with population modeling of striatal neurons using evolutionary optimization algorithms to design 'virtual drugs'. We introduce efficacy metrics to score populations and rank virtual drug candidates. We found virtual drugs using heuristic approaches that performed better than single target modulators and standard classification methods. We compare a real drug to virtual candidates and demonstrate a novel in silico triaging method.


Ulcerative dermatitis in barramundi due to coinfection with Streptococcus iniae and Shewanella algae.
Streptococcus iniae is a pathogenic bacterium which causes septicaemia, while Shewanella algae is an opportunistic pathogen found in marine environments. In this study, we investigated an uncommon coinfection of these 2 bacterial species which resulted in systemic disease and cutaneous ulcers in a barramundi Lates calcarifer farm in the Persian Gulf, Iran. Culture, molecular and histopathological specimens were taken from different organs. In histopathology, results indicated deep bacterial ulceration of skin and subcutaneous muscles. Haemorrhage and hyperaemia were the most common signs observed in visceral organs. In culture, Gram-positive cocci were grown from visceral organs while Gram-negative bacilli were isolated from ulcers. In molecular examination, Streptococcus iniae and Shewanella algae were identified from visceral and ulcer samples, respectively, by PCR of the 16S rRNA gene. The disk diffusion method was used to determine antimicrobial susceptibility of isolated bacteria, with Shewanella algae being resistant to most routinely used antibiotics. In this study, a mixed infection of 2 bacterial species was found; we conclude that systemic streptococcosis could act as a predisposing factor for Shewanella penetration into skin and subsequent ulcer formation. Coinfections are very common in mammals; however, this subject has received little attention in other species, such as fish, and particularly in aquaculture. This study highlights the potential significance of coinfections in barramundi, the effect on the severity of the disease and the potential for new opportunistic pathogens arising.


[Current status of autologous chondrocyte transplantation].
Autogenous chondrocyte transplantation (ACT) is a promising but disputable new method for the treatment of full thickness hyaline cartilage defects. Neither long-term follow-up studies nor prospective randomised comparative clinical trials exist to measure the outcome. Several bioengeneering companies have emerged (Genzyme, Verigen, Co.don, etc.) and commercialised this new method of ACT which has generated enormous interest. Each company uses its own (secret) protocol for culturing human cartilage cells. These protocols vary considerably from each other with regard to culture media, enzymes and other additives (e.g. antibiotics) used. However, no quality control requirements for the culturing process of cartilage cells have been proposed which the companies have to fulfill. At the time of surgery the treating surgeon has to assume (and hope) that the cultured cells are viable, sterile, active and potent but a control mechanism does not exist. Considering the enormous price for ACT which the patients and the insurance companies are asked to pay quality control standards should be developed with the following informations given: cell viability, grade of differentiation, cell morphology, secretion levels of essential matrix components (collagen type II, IX, X and XI, Aggrecan) and the total cell number. None of the above information is currently provided by any of the companies involved. The widespread clinical use of this technique cannot be recommended at this stage as the scientific proof for reproducibility of ACT has not been given so far. The operative technique of ACT is demanding and should only be used by surgeons having attended special practical training courses and workshops to minimise technical failure rates. Clinical results should be documented in a uniform standardised way using established outcome scores and modern diagnostic measures (e.g. intraoperative biomechanical testing of repair tissue). Further controlled clinical trials, experimental research and the establishment of quality control standards are required.


The Brain in (Willed) Action: A Meta-Analytical Comparison of Imaging Studies on Motor Intentionality and Sense of Agency.
Voluntary actions can be fractionated in different phenomena: from the emergence of intentions and the ensuing motor plans and actions, to the anticipation and monitoring of their outcomes, to the appreciation of their congruency with intentions and to the eventual emergence of a sense of agency. It follows that motor intention and the sense of agency should occur at different stages in the normal generation of willed actions. Both these processes have been associated with a fronto-parietal motor network, but no study has investigated to what extent the two experiences can be dissociated for the brain regions involved. To this end, we assessed the PET/fMRI literature on agency and intentionality using a meta-analytic technique based on a hierarchical clustering algorithm. Beside a shared brain network involving the meso-frontal and prefrontal regions, the middle insula and subcortical structures, we found that motor intention and the sense of agency are functionally underpinned by separable sets of brain regions: an "intentionality network," involving the rostral area of the mesial frontal cortex (middle cingulum and pre-supplementary motor area), the anterior insula and the parietal lobules, and a "self-agency network," which involves the posterior areas of the mesial frontal cortex (the SMA proper), the posterior insula, the occipital lobe and the cerebellum. We were then able to confirm this functional organization by a subsequent seed-based fMRI resting-state functional connectivity analysis, with seeds derived from the intentionality/sense of agency specific clusters of the medial wall of the frontal lobe. Our results suggest the existence of a rostro-caudal gradient within the mesial frontal cortex, with the more anterior regions linked to the concept of motor intentionality and the brain areas located more posteriorly associated with the direct monitoring between the action and its outcome. This suggestion is reinforced by the association between the sense of agency and the activation of the occipital lobes, to suggest a direct comparison between the movement and its external (e.g., visual) consequences. The shared network may be important for the integration of intentionality and agency in a coherent appreciation of self-generated actions.


Volatile ester formation in roses. Identification of an acetyl-coenzyme A. Geraniol/Citronellol acetyltransferase in developing rose petals.
The aroma of roses (Rosa hybrida) is due to more than 400 volatile compounds including terpenes, esters, and phenolic derivatives. 2-Phenylethyl acetate, cis-3-hexenyl acetate, geranyl acetate, and citronellyl acetate were identified as the main volatile esters emitted by the flowers of the scented rose var. "Fragrant Cloud." Cell-free extracts of petals acetylated several alcohols, utilizing acetyl-coenzyme A, to produce the corresponding acetate esters. Screening for genes similar to known plant alcohol acetyltransferases in a rose expressed sequence tag database yielded a cDNA (RhAAT1) encoding a protein with high similarity to several members of the BAHD family of acyltransferases. This cDNA was functionally expressed in Escherichia coli, and its gene product displayed acetyl-coenzyme A:geraniol acetyltransferase enzymatic activity in vitro. The RhAAT1 protein accepted other alcohols such as citronellol and 1-octanol as substrates, but 2-phenylethyl alcohol and cis-3-hexen-1-ol were poor substrates, suggesting that additional acetyltransferases are present in rose petals. The RhAAT1 protein is a polypeptide of 458 amino acids, with a calculated molecular mass of 51.8 kD, pI of 5.45, and is active as a monomer. The RhAAT1 gene was expressed exclusively in floral tissue with maximum transcript levels occurring at stage 4 of flower development, where scent emission is at its peak.


MHC antigen expression and cellular response in spontaneous and induced rejection of intracerebral neural xenografts in neonatal rats.
Fetal mouse retinae transplanted to the mesencephalon of neonatal rats generally survive for prolonged periods of time without immune suppression suggesting that such grafts enjoy a degree of immunological privilege. A small, but consistent percentage of these transplants, however, ultimately undergo spontaneous rejection. In addition, rejection can be induced by (1) systemically sensitizing the host to the donor antigens by placing a mouse skin graft or (2) producing a local degenerative process adjacent to the graft by removing the host eye contralateral to the side of the retinal transplant. To elucidate the immunological events that underly spontaneous and induced rejection in this system, we examined the distribution of lymphocytes, astrocytes, microglia, and cells expressing major histocompatibility complex (MHC) antigens in unrejected grafts, in transplants showing spontaneous rejection, and in grafts undergoing induced rejection. In unrejected grafts, increased astrocytic and microglial staining was seen around the photoreceptor layer of the graft and at the graft-host interface, but no lymphocytes and only occasional cells expressing MHC antigens were detected. In contrast, spontaneously rejecting grafts showed widespread MHC, lymphocytic, astrocytic, and microglial immunoreactivity that extended well beyond the limits of the transplant into the surrounding host brain. Skin graft-induced rejection produced a temporally consistent, comparatively localized enhancement of astrocytic, microglial and MHC immunoreactivity and infiltration of lymphocytes. Four to five days after skin grafting, before neural graft rejection was detectable histologically, MHC immunoreactivity was demonstrated within the transplant coinciding with the presence of small numbers of lymphocytes and an increase in microglial staining. By 8 days, grafts had undergone profound necrosis. Intense astrocytosis, microglial staining, MHC immunoreactivity, and perivascular lymphocytic cuffing were present within the graft and at the graft-host interface. With longer survival times, several of these changes were also detected within the visual pathways, suggesting that the regions to which the graft projected were also involved, though in a delayed fashion. After eye removal, the temporal pattern of rejection was more protracted and considerably less uniform than that seen after skin grafting. At 7 days, prominent microglial, astrocytic, and MHC immunoreactivity was seen in the area of distribution of the host optic axons within the superior colliculus and to a lesser extent around the graft itself, however, no infiltration of lymphocytes was detected. With longer survival times, an increasing percentage of grafts showed signs of overt rejection with perivascular cuffing by lymphocytes; however, even at 21 days, a small number of grafts remained free of lymphocytic infiltration, despite the presence of intense MHC, astrocytic, and microglial staining. We conclude that the different rejection models studied may involve fundamentally different triggers of the host immune system, but that in each case MHC expression may be the precedent step to graft rejection.


Mechanism and application of β-adrenoceptor blockers in soft tissue wound healing.
Soft tissue damage stimulates sympathetic nerves to release large amounts of catecholamine hormones which bind to β-adrenergic receptors (β-ARs) on the cell membrane surface. It activates the downstream effector molecules and impairs soft tissue wound healing. β-blockers specifically inhibit β-ARs activation in acute/chronic skin lesions and ulcerative hemangiomas. They also accelerate soft tissue wound healing by shortening the duration of inflammation, speeding keratinocyte migration and reepithelialization, promoting wound contraction and angiogenesis, and inhibiting bacterial virulence effects. In addition, β-blockers shorten wound healing periods in patients with severe thermal damage by reducing the hypermetabolic response. While β-blockers promote/inhibit corneal epithelial cell regeneration and restores limbal stem/progenitor cells function, it could well accelerate/delay corneal wound healing. Given these meaningful effects, a growing number of studies are focused on examining the efficacy and safety of β-blockers in soft tissue wound repair, including acute and chronic wounds, severe thermal damage, ulcerated infantile hemangioma, corneal wounds, and other soft tissue disorders. However, an intensive investigation on their acting mechanisms is imperatively needed. The purpose of this article is to summerize the roles of β-blockers in soft tissue wound healing and explore their clinical applications.


[Inhibition of various stages of DNA replication in sea urchin embryos].
The embryos of the sea urchin Strongylocentrotus intermedius possess the ability to incorporate into their DNAs 2'-deoxynucleosides together with all their bases, i.e., adenine, guanine, cytosine and thymine. This incorporation is inhibited by 3'-amino-2',3'-dideoxynucleosides with the same bases. 5'-Amino-5'-deoxynucleosides and 5'-amino-2',5'-dideoxynucleosides moderately inhibit the incorporation of [3H]2'-deoxynucleosides into the DNAs by competing with the latter, presumably at the phosphorylation stage. The most potent inhibiting effect is exerted by 2'-amino-2'-deoxynucleosides and 2'-asido-2'-deoxynucleosides; the mechanism of this inhibition is still obscure, however.


Setting-based practice variation in the management of simple febrile seizure.
To identify provider-based differences in the ED assessment and management of children presenting with uncomplicated, first-time febrile seizures. Multicenter, retrospective cohort study of seven EDs in-the Chicago area: two tertiary academic pediatric EDs (PEDs) and five community-based general EDs (GEDs). The visits of all patients with a discharge diagnosis including the term "seizure" were identified from a 30-month period. Records of patients who met criteria for simple, first-time febrile seizure were reviewed (age 6-60 months; temperature > or =38.0 degrees C; single, generalized, tonic-clonic seizure <20 minutes; "alert" or "arousable" on presentation; absence of known neurologic disease). Four hundred fifty-five records were included: 330 and 125 patients presenting to GEDs and PEDs, respectively. The two groups did not differ in mean age, vital signs, reported duration of seizure, or prior antibiotic use. Lumbar puncture (LP) was performed more often in the GED group (33% vs 22%). No patients were found to have bacterial meningitis. The patients in the GED group were more likely to receive parenteral antibiotics in the ED (56% vs 22%) and to be admitted or transferred (18% vs 4%). In a logistic regression model incorporating age, temperature, seizure duration, seizure in the ED, prior antibiotic use, primary care, and insurance status, the GED patients remained more likely to have an LP (OR 1.5), receive parenteral antibiotics (OR 2.5), and be admitted or transferred (OR 2.5). There were significant setting-based differences in the evaluation and management of children with simple febrile seizures presenting to GEDs and PEDs.


Disrupted-in-schizophrenia-1 (DISC1) Regulates Endoplasmic Reticulum Calcium Dynamics.
Disrupted-in-schizophrenia-1 (DISC1) has emerged as a convincing susceptibility gene for multiple mental disorders, but its mechanistic link to the pathogenesis of schizophrenia related psychiatric conditions is yet to be further understood. Here, we showed that DISC1 localizes to the outer surface of the endoplasmic reticulum (ER). EXOC1, a subunit of the exocyst complex, interacted with DISC1 and affected its recruitment to inositol-1,4,5-trisphosphate receptor 1 (IP3R1). Notably, knockdown of DISC1 and EXOC1 elicited an exaggerated ER calcium response upon stimulation of IP3R agonists. Similar abnormal ER calcium responses were observed in hippocampal neurons from DISC1-deficient mutant mice. Moreover, perturbation of ER calcium dynamics upon DISC1 knockdown was effectively reversed by treatment with antipsychotic drugs, such as clozapine and haloperidol. These results collectively indicate that DISC1 is a regulatory factor in ER calcium dynamics, linking a perturbed intracellular calcium signaling and schizophrenia pathogenesis.


Fusions involving PAX and FOX genes in the molecular pathogenesis of alveolar rhabdomyosarcoma: recent advances.
Rhabdomyosarcoma is the most frequent soft tissue sarcoma in the pediatric population. Two main histopathologic variants have been described, embryonal (ERMS) and alveolar (ARMS), which demonstrate clinical and genetic differences. In particular, most ARMS but not ERMS tumors are characterized by the presence of recurrent chromosomal translocations, which have been cytogenetically defined as t(2;13)(q35;q14) and t(1;13)(p36;q14). These translocations form PAX3-FKHR and PAX7-FKHR gene fusions, which encode chimeric transcription factors. These chimeric proteins are hypothesized to generate a novel transcriptional program in the target cell, thereby contributing to multiple aspects of ARMS tumorigenesis. This review highlights recent advances in numerous areas of biomedical investigation that are providing new insights into the biology, molecular pathology, and translational science of ARMS: the identification of downstream targets of PAX3-FKHR and collaborating events in the process of tumorigenesis and metastasis; generation of animal models based on the gene fusion and collaborating events; development of new assays for diagnosis, prognosis, and detection of minimal disseminated disease; and exploration of immune recognition of this tumor and the fusion protein. These findings highlight the continued importance of the fusion proteins in understanding the biology of this tumor and developing improved diagnostics for this tumor, and have led to the initiation of efforts to explore therapeutic strategies based on the increasing understanding of the biology of these fusion proteins.


A model of risk of falling for psychogeriatric patients.
One hundred community-dwelling psychiatric outpatients, 60 years and older, were evaluated for factors associated with symptoms of dizziness, falling, and orthostatic hypotension. Thirty-nine percent complained of dizziness or falling, and 34% had systolic orthostatic hypotension. Together, systolic and diastolic blood pressure drop, type of somatic illness, type and number of drugs, and psychiatric diagnosis accounted for 50% of the variance in dizziness and falling. Type of illness, drug category, and psychiatric diagnosis accounted for only 19% of the variance in orthostatic hypotension. Statistical analysis showed that systolic orthostatic hypotension, disease classification, and type and number of drugs taken contribute independently to dizziness and falling. In geriatric psychiatric patients, careful attention to orthostatic hypotension, concurrent somatic illness, and number and type of medication is essential to the prevention of dizziness, falling, and their consequences.


The Japanese Clinical Practice Guideline for acute kidney injury 2016.
Acute kidney injury (AKI) is a syndrome which has a broad range of etiologic factors depending on different clinical settings. Because AKI has significant impacts on prognosis in any clinical settings, early detection and intervention are necessary to improve the outcomes of AKI patients. This clinical guideline for AKI was developed by a multidisciplinary approach with nephrology, intensive care medicine, blood purification, and pediatrics. Of note, clinical practice for AKI management which was widely performed in Japan was also evaluated with comprehensive literature search.


Endometriosis and epithelial ovarian cancer: a two-sample Mendelian randomization analysis.
Endometriosis, a prevalent condition, has long been recognized as a chronic and debilitating ailment affecting an estimated 1790 million women worldwide. Observational studies have established a correlation between endometriosis and ovarian cancer. Thus, we endeavored to employ Two-Sample Mendelian Randomization, utilizing summary statistics from a Genome-Wide Association Study of endometriosis and epithelial ovarian cancer, with genetic markers serving as proxies for epithelial ovarian cancer. The analysis revealed a significant correlation between these entities, with an odds ratio (OR) of 1.23 (95% CI 1.11-1.36). Upon histotype-specific examination, robust evidence emerged for an association of endometriosis with the risk of endometrioid carcinoma (OR 1.49, 95% CI 1.24-1.81), clear cell carcinoma (OR 2.56, 95% CI 1.75-3.73), and low malignant potential tumors (OR 1.28, 95% CI 1.08-1.53). These findings provide a theoretical framework for prospective investigations aimed at enhancing the potential therapeutic efficacy of managing endometriosis in averting the onset and progression of ovarian cancer.


[Oral cancer epidemiology in a public laboratory in Mato Grosso State, Brazil].
This study analyzed oral cancer epidemiology based on histopathology reports from a public laboratory in Mato Grosso, Brazil, after a specific policy was implemented for treating oral and facial diseases in the State. This was a cross-sectional epidemiological study, based on 1,324 histopathology reports issued from January 2005 to December 2006. The study identified 44 cases of oral cancer, or 3% of all oral lesions, and analyzed them in relation to the following variables: histological type, gender, age, and patient's place of residence (capital versus rest of State). The most common histological type was squamous cell carcinoma. Most of the diagnoses occurred in men in their 50s and 60s living in the interior of the State. During two years in operation, this public oral pathology service had recorded a considerable number of oral cancer cases.


Early identification of wound infection: understanding wound odour.
Malodorous wounds can be distressing for patients and their families, negatively impacting on quality-of-life outcomes. For health professionals malodorous wounds can also cause distress manifesting in feelings of disgust when faced with a wound emitting an unpleasant or repulsive odour. There has been investigation into the management of controlling odour particularly in relation to fungating wounds. However, there is limited research that explores techniques for early identification and recognition of wound odours that may be indicative of infection. Electronic nose technology has received some attention, but to date has not been integrated into either diagnostics of infection in wounds or education of health professionals to prepare them for the realities of clinical practice.


Retroflexion, a costless endoscopic maneuver, increases adenoma detection rate in the ascending colon.
Missed polyps during colonoscopy are considered an important factor for interval cancer appearance, especially in the ascending colon (AC). We evaluated the contribution of retroflexion to polyp and adenoma detection in the AC. This prospective observational study included consecutive patients who underwent a complete colonoscopy between 06/2017 and 06/2018. The AC was examined in 2 phases: the first included 2 forward views from the hepatic flexure to the cecum; the second involved a retroflexion in the cecum, inspection up to the hepatic flexure and reinsertion to the cecum. The study included 655 patients, 628 (95.88%) with successful retroflexion (mean age: 62.5±10.8 years, 332 male). Indications for colonoscopy were screening in 33.28%, follow up in 36.03%, and diagnostic assessment in 30.69%. In total, 286 polyps and 220 adenomas were detected in the AC. Phase 1 identified 119 adenomas, yielding an adenoma detection rate (ADR) in the AC of 14.2% (95% confidence interval [CI] 11.52-16.84%) while phase 2 identified 86 additional adenomas, improving the ADR in the AC to 22.75% (95%CI 19.54-25.96%; P<0.01). Adenoma miss rate was 39.1% (86/225) and per-patient adenoma miss rate was 11.15% (73/655). Retroflexion proved beneficial mainly in the upper third of the AC (odds ratio [OR] 4.29, 95%CI 1.84-11.56; P<0.01) and for small (<5 mm) adenomas (OR 1.61, 95%CI 1.02-2.56; P=0.04). Multivariate analysis showed that age >60 years, detection of adenomas in forward views and the indication "follow up" influenced ADR during retroflexion. Retroflexion is a simple and safe maneuver that increases the ADR in the AC and should complete a second forward view.


A score for predicting response to pharmacotherapy in obsessive-compulsive disorder.
Although there have been many attempts to find predictors of therapeutic response to antidepressant treatment of obsessive-compulsive disorder (OCD), few reports have evaluated the joint predictive value of a number of clinical characteristics. This study aimed to identify clinical predictors of outcome in OCD, and to develop an easily applicable method to predict response to drug treatment. One hundred and fifty patients with primary OCD according to DSM-IV criteria were randomly assigned in a 12-week, double-blind, comparison trial with a selective serotonin reuptake inhibitor (paroxetine), and a serotonin-noradrenaline reuptake inhibitor (venlafaxine). The primary efficacy parameter was the Yale-Brown obsessive-compulsive scale (Y-BOCS) score, and response to treatment was prospectively defined as a >/= 35% decrease from the beginning. A stepwise multivariate analysis was used to identify predictors. The absence of previous therapies, moderate baseline severity of obsessive-compulsive symptoms (Y-BOCS score < 23), and low Hamilton Depressive Rating Scale scores (6-15) were found to be prognostic determinants of good response to pharmacotherapy. The prognostic ability of the prediction model to discriminate between responders and non-responders was quantified as the area under the receiver operating/operator characteristic curve (ROC area), which was 0.71 (95% confidence interval 0.63-0.8), demonstrating a reasonable discriminatory power. This study is the first to present a model that can estimate by the use of prediction rules the probability of treatment response to antidepressants in patients with OCD.


Drosophila neurexin IV interacts with Roundabout and is required for repulsive midline axon guidance.
Slit/Roundabout (Robo) signaling controls midline repulsive axon guidance. However, proteins that interact with Slit/Robo at the cell surface remain largely uncharacterized. Here, we report that the Drosophila transmembrane septate junction-specific protein Neurexin IV (Nrx IV) functions in midline repulsive axon guidance. Nrx IV is expressed in the neurons of the developing ventral nerve cord, and nrx IV mutants show crossing and circling of ipsilateral axons and fused commissures. Interestingly, the axon guidance defects observed in nrx IV mutants seem independent of its other binding partners, such as Contactin and Neuroglian and the midline glia protein Wrapper, which interacts in trans with Nrx IV. nrx IV mutants show diffuse Robo localization, and dose-dependent genetic interactions between nrx IV/robo and nrx IV/slit indicate that they function in a common pathway. In vivo biochemical studies reveal that Nrx IV associates with Robo, Slit, and Syndecan, and interactions between Robo and Slit, or Nrx IV and Slit, are affected in nrx IV and robo mutants, respectively. Coexpression of Nrx IV and Robo in mammalian cells confirms that these proteins retain the ability to interact in a heterologous system. Furthermore, we demonstrate that the extracellular region of Nrx IV is sufficient to rescue Robo localization and axon guidance phenotypes in nrx IV mutants. Together, our studies establish that Nrx IV is essential for proper Robo localization and identify Nrx IV as a novel interacting partner of the Slit/Robo signaling pathway.


Psychiatry clerkship: a review of the concept.
The concept of psychiatric clerkships as part of undergraduate medical education was examined. All relevant English literature from the last eight years was surveyed and discussed in four parts: 1) The goals and objectives of psychiatric clerkships were examined. The author concluded that there is a need to further differentiate educational goals of the clinical years from the pre-clinical years. Two major requirements for a successful clerkship were patient responsibility and adequate faculty supervision. 2) The significance of the clerkship setting was evident from the survey as settings were found to influence the students' attitudinal development and also the development of clinical judgement. 3) The effects of psychiatric clerkships on the students, patients, and faculty were discussed and felt to be an requiring further exploration. 4) The problems of evaluation were addressed. From the survey, it appeared that the clerkship experience was of particular value in modifying student attitudes to mental illness. Attempts to evaluate the acquisition of clinical skills and judgement were reviewed. The paper concluded by outlining areas requiring further exploration and research so that the concept of psychiatric clerkships can be further developed.


Validity of probands' reports and self-reports of essential tremor: Data from a large family study in North America.
The search for genes for essential tremor (ET) is active. Researchers often depend on probands' reports or self-reports to assign disease status to relatives. Yet there are surprisingly few data on the validity of these reports. In two prior studies, with small sample sizes, validity was poor (sensitivity = 16.7-43.3%). In the current study, ET probands and their relatives were screened for tremor and then underwent a videotaped in-person neurological examination. One investigator then assessed the screening questionnaires and videotapes to assign diagnoses of ET, borderline tremor or other diagnosis. There were 98 probands and 243 relatives (105 with ET, 34 with borderline tremor). Educational attainment was high (15.6 ± 2.7 years). Probands failed to report tremor in 39/139 relatives with ET or borderline tremor; conversely, they reported tremor in 32/104 relatives without ET or borderline tremor. Thus, in total, there were 71/243 (29.2%) mis-identifications. Thirty six of 139 ET and borderline ET cases failed to self-report tremor; conversely, 30/104 relatives without ET or borderline tremor self-reported tremor. Thus, in total, there were 66/243 (27.2%) mis-identifications. In summary, in individuals with greater educational attainment, the validity of reported information on ET was considerably higher than previously reported. Despite this, even among well-educated individuals in North America, probands' reports and self-reports misclassified approximately 30% (i.e., one-in-three) of relatives.


The master of science in nursing curriculum: integrating diversity content within an individual model's paradigm.
Faculty can play an integral role in both facilitating success for diverse student groups and promoting diversity through experiential approaches. A willingness to evaluate your own teaching style for cultural biases is the first step. Once this is done, decide on the culture-general skills as well as the culture-specific skills that are essential for students within your area of specialization. With those outcomes in mind, you can design experiences to develop in students the appreciation of diversity, the skills to interact in a diverse world, and an awareness of the many issues of diversity that exist in our homes, communities, workplace, and society.


Two release rates from monolithic carboxymethyl starch tablets: formulation, characterization, and in vitro/in vivo evaluation.
Most of non-steroidal anti-inflammatory drugs (NSAIDs) including ibuprofen at more than 1200 mg/day may generate gastrointestinal and cardiovascular side effects. Bilayer or multiparticulate devices have been developed for controlled release in order to prevent undesired side effects. A new "two release rate (2RR) monolithic tablets" approach is now proposed for controlled release of poorly soluble drugs, particularly NSAIDs. Ibuprofen was used as model drug. This concept is based on a calcium carboxymethyl-starch (CaCMS) complex as a novel, low-cost excipient for monolithic dosage forms easy to manufacture by direct compaction. The in vitro dissolution from CaCMS formulations (tablets containing 400 or 600 mg active principle) showed two distinct release rates: (i) an initial fast release (for 30 min in simulated gastric fluid) of about 200 mg ibuprofen, an amount similar to the dosage of conventional immediate-release form (Motrin® 200 mg), and (ii) a slow release of remaining about 200 or 400 mg for a period of 12 h. A preliminary in vivo study (beagle dogs) showed pharmacokinetic parameters of one single controlled-release dosage of ibuprofen (400 mg) formulated with CaCMS, near equivalence with multiple doses (three tablets of 200 mg ibuprofen) of conventional Motrin®. A marked reduction (with 33%) of administered dose (400 instead 600 mg) was achieved by the new formulation with equivalent therapeutic effects. This dose reduction may be beneficial and is expected to minimize side damage risks. Although the present study was limited to NSAIDs, the 2RR concept can be applied for other drugs, particularly for subjects unable to follow frequent administrations.


Structure and expression of B-myc, a new member of the myc gene family.
The myc family of genes contains five functional members. We describe the cloning of a new member of the myc family from rat genomic and cDNA libraries, designated B-myc. A fragment of cloned B-myc was used to map the corresponding rat locus by Southern blotting of DNA prepared from rat X mouse somatic cell hybrids. B-myc mapped to rat chromosome 3. We have previously mapped the c-myc to rat chromosome 7 (J. Sümegi, J. Spira, H. Bazin, J. Szpirer, G. Levan, and G. Klein, Nature [London] 306:497-498, 1983) and N-myc and L-myc to rat chromosomes 6 and 5, respectively (S. Ingvarsson, C. Asker, Z. Wirschubsky, J. Szpirer, G. Levan, G. Klein, and J. Sümegi, Somat. Cell Mol. Genet. 13:335-339, 1987). A partial sequence of B-myc had extensive sequence homology to the c-myc protein-coding region, and the detection of intron homology further indicated that these two genes are closely related. The DNA regions conserved among the myc family members, designated myc boxes, were highly conserved between c-myc and B-myc. A lower degree of homology was detected in other parts of the coding region in c-myc and B-myc not present in N-myc and L-myc. A 1.3-kilobase B-myc-specific mRNA was detected in most rat tissues, with the highest expression in the brain. This resembled the expression pattern of c-myc, although at different relative levels, and was in contrast to the more tissue-specific expression of N-myc and L-myc. B-myc was expressed at uniformly high levels in all fetal tissues and during subsequent postnatal development, in contrast to the stage-specific expression of c-myc.


Generating Bioactive Natural Product-inspired Molecules with Machine Intelligence.
The computer-assisted design of new chemical entities has made a leap forward with the development of machine learning models for automated molecule generation. The overarching goal of this conceptual approach is to augment the creativity of medicinal chemists with a machine intelligence. In this Perspective we highlight prospective applications of "de novo" drug design and target prediction, aiming to generate natural product-inspired bioactive compounds from scratch. A virtual chemist transforms pharmacologically active natural products into new, easily synthesizable small molecules with desired properties and activity. Computational activity prediction and automated compound generation offer the possibility to systematically transfer the wealth of pharmaceutically active natural products to synthetic small molecule drug discovery. We present selected prospective examples and dare a forecast into the future of natural product-inspired drug discovery.


Bone disease in primary hyperparathyroidism.
Bone disease in severe primary hyperparathyroidism (PHPT) is described classically as osteitis fibrosa cystica (OFC). Bone pain, skeletal deformities and pathological fractures are features of OFC. Bone mineral density is usually extremely low in OFC, but it is reversible after surgical cure. The signs and symptoms of severe bone disease include bone pain, pathologic fractures, proximal muscle weakness with hyperreflexia. Bone involvement is typically characterized as salt-and-pepper appearance in the skull, bone erosions and bone resorption of the phalanges, brown tumors and cysts. In the radiography, diffuse demineralization is observed, along with pathological fractures, particularly in the long bones of the extremities. In severe, symptomatic PHPT, marked elevation of the serum calcium and PTH concentrations are seen and renal involvement is manifested by nephrolithiasis and nephrocalcinosis. A new technology, recently approved for clinical use in the United States and Europe, is likely to become more widely available because it is an adaptation of the lumbar spine DXA image. Trabecular bone score (TBS) is a gray-level textural analysis that provides an indirect index of trabecular microarchitecture. Newer technologies, such as high-resolution peripheral quantitative computed tomography (HR-pQCT), have provided further understanding of the microstructural skeletal features in PHPT.


Transition-metal-ion-mediated polymerization of dopamine: mussel-inspired approach for the facile synthesis of robust transition-metal nanoparticle-graphene hybrids.
Inspired by the high transition-metal-ion content in mussel glues, and the cross-linking and mechanical reinforcement effects of some transition-metal ions in mussel threads, high concentrations of nickel(II), cobalt(II), and manganese(II) ions have been purposely introduced into the reaction system for dopamine polymerization. Kinetics studies were conducted for the Ni(2+)-dopamine system to investigate the polymerization mechanism. The results show that the Ni(2+) ions could accelerate the assembly of dopamine oligomers in the polymerization process. Spectroscopic and electron microscopic studies reveal that the Ni(2+) ions are chelated with polydopamine (PDA) units, forming homogeneous Ni(2+)-PDA complexes. This facile one-pot approach is utilized to construct transition-metal-ion-PDA complex thin coatings on graphene oxide, which can be carbonized to produce robust hybrid nanosheets with well-dispersed metallic nickel/metallic cobalt/manganese(II) oxide nanoparticles embedded in PDA-derived thin graphitic carbon layers. The nickel-graphene hybrid prepared by using this approach shows good catalytic properties and recyclability for the reduction of p-nitrophenol.


Cirrhosis, gastrointestinal bleed, and cryptococcal peritonitis.
Disseminated Cryptococcus neoformans infection rarely causes peritonitis in non-HIV-infected patients but does affect cirrhotic patients. Diagnostic challenges delay treatment, and mortality is high. We performed a literature search of proven cryptococcal peritonitis cases in HIV-negative adults with underlying cirrhosis, included our own case, and collected demographic, infection risk factor, diagnostic, treatment, and outcomes data. We identified 16 articles and 21 cases. Most patients were men. Alcohol abuse was the leading cause of underlying cirrhosis (n = 10, 48%). Eight (38%) patients experienced an upper gastrointestinal bleed (UGIB) within a month before peritonitis presentation. Peritoneal fluid analysis was abnormal and lymphocytic predominant. Half the patients were fungemic. When performed, peritoneal fluid cryptococcal antigen (CrAg) test results were positive. Amphotericin B was the primary treatment. Mortality was high at 76%. In conclusion, C. neoformans is an opportunistic pathogen that causes peritonitis in non-HIV, cirrhotic patients. People with recent UGIB seem to be at risk. Cryptococcus species infection should be suspected in patients with clinical signs and symptoms of spontaneous bacterial peritonitis whose lymphocytic-predominant peritoneal fluid and cultures are negative for bacterial growth. Peritoneal CrAg testing expedites diagnosis because growth on fungal media is slow. Mortality remains high, despite standard therapy with amphotericin B.